The present disclosure relates to diagnostic and therapeutic conjugates and use of such conjugates to diagnose and treat cancer. More particularly, the present disclosure relates to biomedical polymer nanoconjugates and their use to diagnose and treat cancer.
Cancer (malignant neoplasm) is the number two killer of people in the U.S. Each year in the U.S. more than a million people are diagnosed with cancer and half of those will ultimately die from the disease. Cancer occurs when normal living mammalian cells undergo neoplastic (malignant) transformation. Cancer is tenacious in its ability to uncontrollably and rapidly metastasize throughout the mammalian body, thus giving rise to a high mortality rate.
Cancer cure rates have increased dramatically over the years. This positive trend is a result of the widespread use of improved screening procedures that often lead to the early diagnosis/detection of cancer. However, as more selective treatment strategies have been developed, it is necessary to develop new and improved early stage clinical diagnostic procedures that can be used far earlier to determine a potential treatment strategy based on the biological properties and proliferation of the cancer. In addition, it is desired to develop non-invasive procedures that can be used for determining either a positive or negative response to a treatment strategy as early as possible thus extending the mammalian host's viability.
The first step in clinically treating cancer is to accurately diagnose the location and presence of the disease. This means determine the location of the cancer and confirm that the suspected cancer is cancer. The area of the body where the tumor or cancer is identified using symptomatology reports from a patient and then x-rays or other diagnostic tools are utilized to verify the initial symptoms and to identify the specific location of the cancer. That the location is cancerous is ultimately determined from a biopsy. Examination of a sample of suspected cancerous growth by a cancer specialist examining the biopsy confirms that the tissue is either benign or it is malignant cancer and if it is cancer, then what type of cancer and what the stage of development of the cancer is determined. Non-invasive imaging techniques are revolutionizing understanding diseases at the cellular and molecular levels. However, more is needed.
Among the current available non-invasive imaging modalities, positron emission tomography (PET) has demonstrated its great potential in the field of molecular imaging due to its superior sensitivity and specificity in diverse applications, the very small amount of agent required and the ability to quantitatively analyze the regions of interest. Since the completion of human genome sequence, there have been considerable research interests in the assessment of gene functions and protein-protein interactions non-invasively using molecular imaging approaches. Of the various PET probes that have been developed to image gene expression in small animal models, oligonucleotides appear to be an inexhaustible gold mine for the development of new tracers with high specificity considering that an oligonucleotide with more than 12 nucleobases could represent a unique sequence in the whole human genome with a gene number estimated between 24,000 and 30,000, and alternative polyadenylation and splicing could result in a number of messenger ribonucleic acid (mRNA) between 46,000 and 85,000.
The techniques of antisense mRNA originated from the natural modulation of gene replication and expression in bacteria via small complementary RNA molecules in an opposite direction (antisense). However, the naturally occurring oligonucleotides with 2′-deoxyphosphodiester cannot be directly applied to nuclear imaging because they are rapidly degraded in vivo by endo- and exo-nucleases. To increase the in vivo stability of oligonucleotides without significant alteration of their pharmacokinetics and targeting properties, many chemical modifications have been made to the sugar-phosphate backbone, including morpholino, phosphorothioate, phosphoroamidate, methylphosphonate, 2′- or 3′-modified derivatives, peptide nucleic acids (PNAs), and locked nucleic acids. Peptide nucleic acids (PNAs) are a unique type of oligonucleotides, which was initially introduced by Nielsen et al. in 1991 as ligands for the double stranded DNA recognition. They are synthetic DNA mimics featuring a chain with repeating N-(2-aminoethyl)glycine units instead of the sugar-phosphate backbone.
Due to the structural characteristics (e.g., neutrality and flexibility), PNAs are resistant to the in vivo enzymatic degradation. PNAs bind complementary DNAs or RNAs with high affinity and specificity even under low ionic strength conditions. Recent work has shown that PNAs can be used as molecular hybridization probes, and nuclear imaging tracers.
Using antisense PNAs as molecular imaging probes has a major obstacle in that they have very poor permeability across biologic membranes, which is inherent from their structural feature. Therefore for the hybridization of an unmodified PNA with its target mRNA molecule in vitro, it often requires that the PNA be physically injected into the intracellular plasma. Attempts to overcome this obstacle have been resorted to the drug-delivery techniques, which include using cationic lipids (or polyamines) and liposomes, nanoparticles, and direct conjugation with monoclonal antibody or peptides, etc. Recently it was reported that PNAs with four lysines at the C terminus (PNA-K4 oligomers) demonstrated sequence-specific antisense activity in most tissues that expressed a specific gene.
Radionuclides such as 60Cu, 61Cu and 64Cu among other radionuclides respectively are utilized extensively in the diagnosis and treatment of cancer in living mammals. These radionuclides are useful for diagnosis (60Cu, 61Cu and 64Cu); internal radiation therapy (61Cu and 64Cu) because of their positron—emission and/or toxicity to cancer and their characteristic intermediate half-life and multiple decay mode. Such diagnostic and therapeutic efforts against cancer include the effective administration of radiolabeled chemicals using highly purified 60Cu, 61Cu and 64Cu. 64Cu is particularly useful. The principal advantage to such use is that the radionuclide identifies a location for the cancer as well as provides a cytotoxic effect against the cancer.
Synthetic methodologies are enabling advances in the design of polymeric materials that actively control cellular and physiologic responses. These methods produce materials that are incorporated into scaffolds adaptive to body blood lumens and capable of performing specific functions while being minimally detrimental to normal cellular processes and surrounding tissues for use in therapeutic, drug delivery, and tissue engineering applications.
However, a need continues to exist for enhanced methods that can more accurately diagnose cancer and more particularly assess the response to anticancer therapy, as such methods would have a significant positive impact on determining optimal therapy for treating cancer patients. Also new methods are needed to treat cancer.
So despite the aforegoing remarkable advances and other advances in cancer diagnostics and cancer detection technology, it remains highly desirable to have an enhanced cancer detection and treatment system for use in a living mammal such as in a living human.